The Limits of Two-Year Bioassay Exposure Regimens for Identifying Chemical Carcinogens
Huff, James, Jacobson, Michael F., Davis, Devra Lee, Environmental Health Perspectives
BACKGROUND: Chemical carcinogenesis bioassays in animals have long been recognized and accepted as valid predictors of potential cancer hazards to humans. Most rodent bioassays begin several weeks after birth and expose animals to chemicals or other substances, including workplace and environmental pollutants, for 2 years. New findings indicate the need to extend the timing and duration of exposures used in the rodent bioassay.
OBJECTIVES: In this Commentary, we propose that the sensitivity of chemical carcinogenesis bioassays would be enhanced by exposing rodents beginning in utero and continuing for 30 months (130 weeks) or until their natural deaths at up to about 3 years.
DISCUSSION: Studies of three chemicals of different structures and uses--aspartame, cadmium, and toluene--suggest that exposing experimental animals in utero and continuing exposure for 30 months or until their natural deaths increase the sensitivity of bioassays, avoid false-negative results, and strengthen the value and validity of results for regulatory agencies.
CONCLUSIONS: Government agencies, drug companies, and the chemical industry should conduct and compare the results of 2-year bioassays of known carcinogens or chemicals for which there is equivocal evidence of carcinogenicity with longer-term studies, with and without in utero exposure. If studies longer than 2 years and/or with in utero exposure are found to better identify potential human carcinogens, then regulatory agencies should promptly revise their testing guidelines, which were established in the 1960s and early 1970s. Changing the timing and dosing of the animal bioassay would enhance protection of workers and consumers who are exposed to potentially dangerous workplace or home contaminants, pollutants, drugs, food additives, and other chemicals throughout their lives.
KEY WORDS: animal cancer tests, aspartame, bioassay designs, bisphenol A. cadmium, carcinogenicity, chemical carcinogens, genistein, toluene, toxicology. Environ Health Perspect 116:1439-1442 (2008). doi: 10.1289/ehp.10716 available via http://dx.doi.org/ [Online 30 June 2008]
Additional research on molecular end points and other biological approaches has been recommended for evaluating the toxicity of chemicals (Committee on Toxicity Testing and Assessment of Environmental Agents 2007). However, currently and for the foreseeable future, short-and long-term bioassays represent the most reliable way to evaluate and profile the toxicology of chemicals to which humans are exposed, especially for predicting and preventing long-term adverse exposure effects, including cancer. We focus here on two potentially important means of increasing the sensitivity of carcinogenesis bioassays for identifying potentially carcinogenic food additives, pesticides, workplace chemicals and contaminants, pharmaceuticals, industrial chemicals, consumer products, and other natural and synthetic chemicals.
Chemical carcinogenesis bioassays in animals have long been recognized and accepted as valid predictors of potential cancer hazards to humans (Huff 1999.2002; Rall 2000; Tomatis 2006; Tomatis and Huff 2002). The relevance of experimental bioassays to humans rests on four well-accepted observations: a) Experimental animals and humans are mammals sharing many basic genetic, pharmacologic, toxicologic, and carcinogenic responses; b) findings from independently conducted bioassays on the same chemicals are consistent; c) all known human carcinogens that have been tested adequately are also carcinogenic in animals and, almost without exception, share identical target sites; and d) nearly one-third of human carcinogens were first discovered to induce cancer in animals (e.g., 1,3-butadiene, diethylstilbestrol, dioxins, ethylene oxide, 2-naphthylamine, formaldehyde, vinyl chloride), although most of these were not regulated until human evidence mounted. Thus, in light of the fact that animal bioassays predict human cancer risks, conducting more sensitive tests would better protect the public, and especially workers, from involuntary exposure to animal carcinogens. …